This invention relates to proteins capable of inducing vasodilation and temporary immune suppression in mammals, to compositions containing such proteins, to methods for producing the proteins using peptide synthesis and recombinant DNA techniques, and to synthetic forms of such proteins. The invention also relates to a method of desensitizing a mammal to the effects of an immunogen by administering certain peptides which temporarily inactivate the immune system.
Vasodilators are drugs useful in the treatment of various conditions characterized by constricted blood vessels. Such conditions include Raynaud's syndrome, certain post surgical complications of brain surgery involving sub arachnoid hemorrhage, heart failure, angina pactotis, and hypertension. Recently, the neuropeptide calcitonin gene-related peptide (CGRP) has been characterized as the most powerful and persistent vasodilator known. Calcitonin, another neuropeptide known primarily for its ability to prevent bone loss during periods of calcium stress, is derived from the same gene as CGRP. Despite weak structural homologies, there is enough similarity in the conformations of calcitonin and CGRP that they interact at each other's receptors. Thus, CGRP has a weak calcitonin-like effect on bone (Zaidi et al., Ouart. J. Exp. Pasteur, 72:371 (1987)).
The macrophage, a large phagocytic cell of the reticuloendothelial system, plays a central role in the induction and expression of cellular immunity. Antigen processing and subsequent presentation of antigen by macrophages in the presence of class II histocompatibility antigens can trigger helper T-lymphocyte response (Buss et al., Immunol. Rev. 98:115 (1987). In addition, macrophages can control T-cell responses via production of cytokines such as IL-1 (Unanue et al., Ann, L'institute PaSteur 138:489 (1987)).
Activation of macrophages enhances the microbicidal and tumoricidal activity of the cells, an event which is paralleled by significant changes in the levels of various intracellular, secreted and cell surface proteins (Adams et al., Ann, Rev. Immunol. 2:283 (1984)). For example, levels of secreted IL-1 and expressed class II histocompatability antigen rise, (Adams et al., ibid.) while the level of 5' nucleotidase has been shown to fall (Johnson et al., J. Immunol. 131:1038 (1983)). In addition, the production of H.sub.2 O.sub.2 by activated macrophages is increased over controls (Adams et al., ibid.). Macrophages can be activated by a number of lymphokines such as IFN-.gamma. (Merry et al., J. Immunol. 134:1619 (1985)), and by bacterial cell wall products such as lipopolysaccharide (Pabst et al., J. Exp. Med. 151:101 (1980)). Recently, it has been suggested that as activated macrophages sterilize the site of inflammation they are deactivated so as to avoid possible damage to host tissue via continued release of cytotoxic products. (Tsunawaki et al., Nature 334:260 (1988)).
A first object of this invention is to provide proteins derived from the salivary lysate of the sand fly Lutzomyia longipalpis capable of vasodilation and of temporary immune suppression in mammals. Other objects are to characterize the protein, to provide natural and recombinant forms of the protein, and to provide genes encoding the protein and methods for production of the protein using recombinant DNA and peptide synthesis techniques. A second object is to provide methods for desensitizing a mammal to the effects of an immunogen by administering the protein derived from Lutzomyia, CGRP, calcitonin, active analogs, or synthetic forms thereof.